Ординатура / Офтальмология / Английские материалы / Corneal Dystrophies_Lisch, Seitz_2011
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Differential Diagnosis of SCD
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Differential Diagnosis of SCD |
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Jayne S. Weiss, MD
Chair of Department of Ophthalmology
Herbert Kaufman, Professor of Ophthalmology Louisiana State University Health Science Center 2020 Gravier Street, New Orleans, LA 70112 (USA) E-Mail jayneweiss@aol.com
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Lisch W, Seitz B (eds): Corneal Dystrophies.
Dev Ophthalmol. Basel, Karger, 2011, vol 48, pp 97–115
Clinical and Basic Aspects of Gelatinous
Drop-Like Corneal Dystrophy
Satoshi Kawasaki Shigeru Kinoshita
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Abstract
Gelatinous drop-like corneal dystrophy (GDLD) was first reported in 1914 as a peculiar corneal dystrophy with an autosomal recessive inheritance mode. GDLD is rare in many countries, but relatively prevalent in Japan. The typical finding of GDLD is grayish, mulberry-like, protruding subepithelial depositions with a prominent hyperfluorescence of the cornea. Histologically, GDLD corneas are characterized by subepithelial amyloid depositions that were identified as lactoferrin by amino acid sequencing analysis. In 1998, the TACSTD2 gene was identified as a causative gene for this disease through a linkage analysis and a candidate gene approach. To date, 14 reports have demonstrated 21 mutations comprised of 9 missense, 6 nonsense, and 6 frameshift mutations from 9 ethnic backgrounds. Currently, it is hypothesized that the loss of TACSTD2 gene function causes decreased epithelial barrier function, thereby facilitating tear fluid permeation into corneal tissue, the permeated lactoferrin then transforming into amyloid depositions via an unknown mechanism. For the visual rehabilitation of patients with GDLD, ophthalmologists currently employ various types of keratoplasties; however, almost all patients will experience a recurrence of the disease within a few years after such interventions. Wearing of a soft contact lens is sometimes considered as an alternative treatment for GDLD.
Gelatinous drop-like corneal dystrophy (GDLD, MIM No. 204870) was first described in 1914 as a rare, inheritable corneal dystrophy characterized by subepithelial amyloid depositions [1]. This disease has notable features compared to other inherited corneal dystrophies. Firstly, there is a wide range of clinical appearances of GDLD, while the range of clinical appearances of most of the other inheritable corneal dystrophies is limited. Also, while the amyloid depositions of other corneal amyloidoses are derived from mutated protein of their causative genes, those of GDLD are not derived from the protein products of its causative gene but from other proteins. In addition, this disease is much more prevalent in Japan than in other countries, possibly due to the high frequency of consanguineous marriage in Japan. Here, we describe the clinical and basic aspects of GDLD.
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Fig. 1. a A slit lamp microscope photograph of the hyperfluorescence of the cornea in a GDLD patient. Note that the hyperfluorescent region covers almost the entire cornea as well as the limbus. b A slit lamp microscope photograph demonstrating a GDLD cornea that underwent keratoplasty. The triangle represents the boundary between the host corneal epithelium and the donated corneal epithelium. Note that the host corneal epithelium demonstrates hyperfluorescence while that of the donated cornea does not. c A bar graph demonstrating fluorescein uptake among several corneal dystrophies. GCD = Granular corneal dystrophy; LCD = lattice corneal dystrophy type I; MCD = macular corneal dystrophy. Note that fluorescein uptake is significantly increased in the GDLD cornea.
Clinical Features
General Clinical Properties
Clinical symptoms of GDLD include significant decrease in vision, photophobia, irritation, redness, and tearing. This disease is rare in many countries, but predominant in Japan. The prevalence rate of this disease was estimated as 1 in 31,546 from the frequency of parental consanguinity [2, 3], and the inheritance mode of this disease is autosomal recessive. The typical finding of this disease is grayish, mulberry-like, protruding subepithelial depositions which are mainly located at the central region of bilateral corneas. The onset of this disease characteristically occurs between the first and second decade of the patient’s life. Typically, the corneal lesions will gradually increase in size and number and coalesce with age [4, 5]. Neovascularization of the subepithelial and superficial stroma frequently becomes evident in the very later stages [6]. One of the most prominent clinical features of this disease is increased fluorescence permeation of the corneal epithelium (fig. 1) [7], and it is almost always observed in this disease.
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Fig. 2. An array of slit lamp microscope photographs demonstrating phenotypic variations of GDLD corneas: mulberry type (a), band keratopathy type (b), and kumquat-like type (c).
Subclassification of GDLD
It has been reported that GDLD can be clinically divided into 4 subtypes by the appearance of corneal opacities [8]. These subtypes include the mulberry type (fig. 2a), the band keratopathy type (fig. 2b), the kumquat-like type (fig. 2c), and stromal opacity type. Among them, the 2 predominant clinical forms are the mulberry type and the band keratopathy type. As to the causative factors of such phenotypic variations, the varying sites of mutation were initially thought to be the reason; however, in that report the authors found no apparent difference among these 4 subtypes. In addition, there have been reports demonstrating the existence of GDLD patients who have one phenotype in one eye yet a different phenotype in their other eye [8, 9]. Moreover, a previous report demonstrated the existence of a patient with band keratopathy that changed into GDLD over a 2-year period [10]. Furthermore, a previous report demonstrated the existence of a GDLD family with 1 member suffering from 1 GDLD subtype and another member suffering from a different GDLD subtype [11]. There has also been a report demonstrating a phenotypic transition from the band keratopathy type to the typical mulberry type GDLD 2 years after lamellar keratoplasty [12]. These observations strongly support the notion that the critical factors for determining the GDLD phenotype may hinge on environmental factors rather than genetic backgrounds. Some unknown factors may interfere with the process of amyloid formation, thereby affecting the phenotype of GDLD corneas. It is also speculated that such phenotypic variations are reflective of differences in the stage of GDLD. The mulberry type and the band keratopathy type tend to occur in the early to intermediate stage, while the kumquat-like type tends to occur in the very later stage.
Differential Diagnosis
The diagnosis of GDLD is frequently difficult and even cornea experts may make a misdiagnosis because its clinical appearance is not always typical but sometimes widely varied as mentioned above. The band keratopathy type GDLD exhibits an appearance that is easily confused with ‘true’ band keratopathy, and hence it is very probable that most patients with this GDLD subtype are misdiagnosed as such
Gelatinous Drop-Like Corneal Dystrophy |
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common corneal dystrophy. In addition, this GDLD subtype is sometimes misdiagnosed as spheroid degeneration, a rare corneal dystrophy which mainly affects men who work outdoors [13]. The kumquat-like type GDLD may sometimes be misdiagnosed as lipid degeneration of the cornea from the appearance of its corneal opacity. Gelatino-lattice corneal dystrophy, a rare form of TGFBI-related corneal dystrophy [14], also clinically resembles GDLD. Secondary amyloidosis sometimes presents an appearance that is confused with that of GDLD.
For the accurate diagnosis of GDLD differentially from these confusing diseases, the most important clinical manifestation appears to be hyperfluorescence of the cornea, as GDLD corneas always present a prominent finding while the diseases that GDLD is confused with do not. However, there are some misleading conditions which demonstrate a hyperfluorescence of the cornea at a level comparable to that of GDLD. One such example is drug toxicity. GDLD patients are sometimes misdiagnosed with drug toxicity, especially when they do not present apparent amyloid depositions in their corneas. However, there are various ways to discriminate between drug toxicity and GDLD. Superficial punctate keratopathy is generally found in drug toxicity but not in GDLD. In addition, in GDLD, the hyperfluorescent area not only covers the whole cornea but also extends to some areas of the limbus, while the limbus is not involved in drug toxicity. Moreover, cases of drug toxicity frequently involve the administration of multiple drugs, while those of GDLD normally do not.
For the discrimination of GDLD from the gelatino-lattice corneal dystrophy, mutation analysis of the TACSTD2 and TGFBI genes is valuable. Most secondary amyloidosis patients present the amyloid depositions in one eye while GDLD normally affects both eyes. In addition, eyelash adherence to the area of the amyloid depositions is frequently found in patients with this disease, and hence that finding is of great diagnostic value.
Examination
Routine examinations such as slit lamp biomicroscopy, visual acuity testing, and tonometry are not sufficient for the diagnosis of GDLD. For an accurate diagnosis of this disease differentially from the above-mentioned confusing diseases, the most reliable and valuable examination is undoubtedly the mutation analysis of the TACSTD2 gene. If the detected mutation is one of which was previously reported (table 1) [15] or one that may lead to potentially pathological protein alteration, the diagnosis will almost assuredly be that of GDLD. Therefore, the molecular diagnosis should be performed as thoroughly as possible (Appendix). However, and quite unfortunately, this type of examination is not available in most hospitals, even in advanced countries.
Another important examination is the above-mentioned fluorescent permeation test. This test is easily performed in a standard clinical setting, with minimal invasion for the patient, and thus should be performed prior to performing the molecular diagnosis. When the fluorescent dye is applied to a conjunctival sac of patients with this disease, the dye will immediately permeate into the corneal tissue of GDLD, even
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Kawasaki · Kinoshita |
Table 1. A list of mutations of the TACSTD2 gene that have been reported to date
Nucleotide change |
Amino acid |
Original |
Ethnic |
References |
|
change |
description |
origin |
|
|
|
|
|
|
c.2T>G |
p.Met1Arg |
M1R |
India |
22 |
|
|
|
|
|
c.198C>A |
p.Cys66X |
C66X |
Iran |
15 |
|
|
|
|
|
c.250A>T |
p.Lys84X |
K84X |
Japan |
30 |
|
|
|
|
|
c.322T>C |
p.Cys108Arg |
C108R |
Japan |
30 |
|
|
|
|
|
c.341T>G |
p.Phe114Cys |
F114C |
Iran |
15 |
|
|
|
|
|
c.352C>T |
p.Gln118X |
Q118X |
Japan, |
11, 21, 24, |
|
|
|
China |
26, 27, 29, 31 |
|
|
|
|
|
c.352C>G |
p.Gln118Glu |
Q118E |
India |
22 |
|
|
|
|
|
c.355T>A |
p.Cys119Ser |
C119S |
Tunisia |
22 |
|
|
|
|
|
c.493_494insCCACCGCC |
p.Gly165AlafsX15 |
9-bp ins |
India |
22 |
|
|
|
|
|
c.509C>A |
p.Ser170X |
S170X |
Japan |
21 |
|
|
|
|
|
c.519dupC |
p.Ala174ArgfsX43 |
520insC |
Estonia |
32 |
|
|
|
|
|
c.551A>G |
p.Tyr184Cys |
Y184C |
China |
27 |
|
|
|
|
|
c.557T>C |
p.Leu186Pro |
L186P |
Japan, |
15, 29 |
|
|
|
Iran |
|
|
|
|
|
|
c.564delC |
p.Lys189SerfsX82 |
870delC |
Europe |
22 |
|
|
|
|
|
c.581T>A |
p.Val194Glu |
V194E |
India |
22 |
|
|
|
|
|
c.619C>T |
p.Gln207X |
Q270X |
Japan |
21 |
|
|
|
|
|
c.632delA |
p.Gln211ArgfsX60 |
632delA |
Japan |
21 |
|
|
|
|
|
c.653delA |
p.ASP218ValfsX53 |
c.653delA |
Turkey |
28 |
|
|
|
|
|
c.679G>A |
p.Glu227Lys |
E227K |
Iran |
15 |
|
|
|
|
|
c.772_783delATC |
p.Ile258X |
772 to |
Vietnam |
31 |
TATTACCTGinsT |
|
783del(ATCTAT |
|
|
|
|
TACCTG) + 772insT |
|
|
|
|
|
|
|
c.811delA |
p.Lys271SerfsX26 |
1117delA |
Tunisia |
22 |
|
|
|
|
|
Notational conventions for the nucleotide change and amino acid change follow the guidelines for mutation nomenclature proposed by the Human Genome Variation Society.
Gelatinous Drop-Like Corneal Dystrophy |
101 |